C/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis

Homeobox A9 (HOXA9) is a homeodomain-containing transcrip-tion factor that plays a key role in hematopoietic stem cell expan-sion and is commonly deregulated in human acute leukemias. Avariety of upstream genetic alterations in acute myeloid leukemia(AML) lead to overexpression of HOXA9, almost always in associ-ation with overexpression ofitscofactormeis homeobox 1(MEIS1).A wide range of data suggests that HOXA9 and MEIS1 play a syn-ergistic causative role in AML, although the molecular mechanismsleading to transformation by HOXA9 and MEIS1 remain elusive. Inthis study, we identify CCAAT/enhancer binding protein alpha (C/EBPα) as a critical collaborator required for Hoxa9/Meis1-mediatedleukemogenesis. We show that C/EBPα is required for the prolif-eration of Hoxa9/Meis1-transformed cells in culture and that lossof C/EBPα greatly improves survival in both primaryand secondarymurine models of Hoxa9/Meis1-induced leukemia. Over 50% ofHoxa9 genome-wide binding sites are cobound by C/EBPα, whichcoregulates a number of downstream target genes involved in theregulation of cell proliferation and differentiation. Finally, weshow that Hoxa9 represses the locus of the cyclin-dependent ki-nase inhibitors Cdkn2a/b in concert with C/EBPα to overcomea block in G1 cell cycle progression. Together, our results suggesta previously unidentified role for C/EBPα in maintaining the pro-liferation required for Hoxa9/Meis1-mediated leukemogenesis.